[go: up one dir, main page]

US4004007A - 2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles - Google Patents

2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles Download PDF

Info

Publication number
US4004007A
US4004007A US05/603,222 US60322275A US4004007A US 4004007 A US4004007 A US 4004007A US 60322275 A US60322275 A US 60322275A US 4004007 A US4004007 A US 4004007A
Authority
US
United States
Prior art keywords
compound
sub
phenylmethylene
hydrogen
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US05/603,222
Inventor
John Krapcho
Chester Frank Turk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ER Squibb and Sons LLC
Original Assignee
ER Squibb and Sons LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Priority to US05/603,222 priority Critical patent/US4004007A/en
Priority to GB31485/76A priority patent/GB1541079A/en
Priority to CA258,397A priority patent/CA1076575A/en
Priority to DE19762635278 priority patent/DE2635278A1/en
Priority to FR7623991A priority patent/FR2320094A1/en
Priority to JP51094414A priority patent/JPS5914025B2/en
Application granted granted Critical
Publication of US4004007A publication Critical patent/US4004007A/en
Priority to BE0/196446A priority patent/BE877886Q/en
Priority to HK746/79A priority patent/HK74679A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration

Definitions

  • the present invention is directed to compounds of the formula ##STR2## and N-oxides and acid addition salts thereof, wherein X 1 and X 2 can be the same or different and are hydrogen, F, C1, lower alkyl, lower alkoxy, or CF 3 ; R is H or lower alkyl, A is straight or branched chain alkylene of 2 to 8 carbons, and B is a 5-, 6- or 7-membered heterocyclic ring which includes a nitrogen atom, and may include the other hetero atom such as sulfur, nitrogen or oxygen.
  • the foregoing compounds possess anti-inflammatory activity.
  • this invention encompasses the methods for preparing said compounds, pharmaceutical compositions containing said compounds and methods for using said compositions as anti-inflammatory agents.
  • lower alkyl is intended to mean a straight or branched hydrocarbon fragment of from one to six carbon atoms.
  • lower alkoxy is intended to mean “lower alkyl-O-”.
  • B is a 5-, 6- or 7-membered heterocyclic ring, which includes nitrogen and may include one other hetero atom such as nitrogen, oxygen or sulfur.
  • heterocyclic rings include, but are not limited to, piperidino, homopiperidino, pyrrolidino, morpholino, thiamorpholino, piperazino, N-lower alkyl substituted piperazino or N-hydroxyloweralkylpiperazino.
  • alkylene group represented by A includes straight or branched chain radicals of 2 to 8 carbons, such as --(CH 2 ) 2 --, --(CH 2 ) 4 --, ##STR3## and the like.
  • acid-addition salts is intended to mean salts which may be formed for the purpose of isolation, purification and storage, such as the oxalate salt, etc. and pharmaceutically acceptable salts meant for administration of the compound to a host, such as the hydrochloride, sulfate, acetate, citrate, etc.
  • the new compounds of formula I are prepared by reacting the appropriate cycloalkylone represented by formula ##STR4## with a substituted benzaldehyde of the formula ##STR5## to produce the intermediate of the formula ##STR6##
  • the compounds of formula IV are converted to a compound of formula I by reaction with a hydrazine of the formula ##STR7## in an organic solvent, preferably an alcohol of up to four carbon atoms at temperatures of from about 40° to about 120° C, preferably at about the reflux temperature of the solvent, for from about 1/2 hour to about 12 hours, preferably for about 4 hours.
  • an organic solvent preferably an alcohol of up to four carbon atoms at temperatures of from about 40° to about 120° C, preferably at about the reflux temperature of the solvent, for from about 1/2 hour to about 12 hours, preferably for about 4 hours.
  • the hydrazine of formula V is prepared by reacting a heteroalkylene halide, B-A-halo, with an excess of hydrazine H 2 NNH 2 .
  • compounds of formula IV can be reacted with a hydroxyalkyl hydrazine of the formula ##STR8## to form the alcohol of the formula ##STR9##
  • the alcohol of formula VII is reacted by heating with p-toluenesulfonyl chloride to form the tosylate of formula ##STR10## which in turn is treated with the heterocyclic compound of formula HB to form the compounds of formula I.
  • a compound of formula I may be converted to its N-oxide by reaction with an oxidizing agent such as hydrogen peroxide, peracetic acid and so forth.
  • an oxidizing agent such as hydrogen peroxide, peracetic acid and so forth.
  • the compounds of the present invention are useful as anti-inflammatory agents in mammalian species, e.g., rats and mice, as indicated by the passive cutaneous anaphylaxis test in the rat [Ref: Ovary, Z and Bier, O.G., Proc. Soc. Exp. Biol. Med. 81:584, 1952 and Goose, J. and Blair, A. M. J. N., Immunology, 16:749, 1969], when administered in amounts ranging from about 0.5 mg/kg to about 10.0 mg/kg of body weight per day.
  • a preferred dosage regimen for optimum results is from about 1 mg to about 5 mg per kg of body weight per day, and such dosage units are employed that a total of about 35 mg to about 7 g of active ingredient are administered in a 24-hour period for a subject of about 70 kg body weight.
  • the compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.
  • the active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard of soft gelatin, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like.
  • the amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermin
  • any material may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both.
  • a syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the oxalate salt is converted to the base (K 2 CO 3 ; ether extractions) and the latter (9.3 g) and 2.6 g of maleic acid are dissolved in 60 ml of warm MeCN and diluted to 600 ml with ether. After prolonged rubbing and subsequent cooling, the crystalline maleate salt slowly separates; crude yield, 8.5 g (50%); m.p. 121°-122° (s. 117° ). Crystallization from 60 ml methanol - 700 ml ether gives 7.7 g (45%) of nearly colorless product; m.p. 146°-148° .
  • the heavy lower layer is separated, extracted with ethanol, and the combined ethanol layers are concentrated in a rotary evaporator.
  • the oily residue (11.0 g) is distilled to give 5.8 g (68%) of a colorless oil; b.p. 100°-103° /1 mm.
  • the material is hygroscopic and picks up CO 2 readily.
  • 2,6-Bis(phenylmethylene)cyclohexanone (8.8 g; 0.032 mole) is reacted with the above hydrazine as prepared in part A (5.5 g; 0.032 mole) in 80 ml of methanol as described under Part C of Example 1 to give 16 g of crude oily base.
  • the crude dioxalate salt weighs 16.1 g; m.p. 200°-202° (dec.).
  • the cream colored solid weighs 13.9 g; m.p. 204°-206° (dec.).
  • the dioxalate salt is converted to the base (K 2 CO 3 ; ether extractions) and the latter (8.3 g) and 4.5 g of maleic acid are dissolved in 140 ml of warm MeCN; the solid dimaleate salt separates. After crystallizing at room temperature the mixture is cooled overnight; wt. 12.1 g (65%); m.p. 179°-181° . Crystallization from 30 ml hot DMF - 80 ml MeCN gives 10.7 g (57%) of cream colored material; m.p. 179°-181° .
  • Trimethylene chlorobromide (180 g; 1.15 moles) and 150 g (1.72 moles) of morpholine are reacted in 450 ml of benzene by the method of Adams and Whitmore, JACS, 67, 736 (1945).
  • the solvents instead of extracting with HCl as in the reference, the solvents are evaporated and the residue distilled to give 76.8 g of colorless oil; b.p. 112°-117° /25 mm. Lit. b.p., 113°-115° /25 mm.
  • the product is dissolved in 1.2 1. of ether, cooled, stirred, and treated with 58 ml. of 8.2 N alcoholic HCl to precipitate the solid HCl salt; yield, 81.6 g (36%); m.p. 164°-166° .
  • the active ingredient, starch and magnesium stearate are blended together.
  • the mixture is used to fill hard shell capsules of a suitable size at a fill weight of 485 milligrams per capsule.
  • the active ingredient, lactose and corn starch (for mix) are blended together.
  • the corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 screen and dried at 120° F.
  • the dry granules are passed through a No. 16 screen.
  • the mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.
  • the sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein.
  • the sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution.
  • the volume is adjusted to 100 milliliters with distilled water.
  • a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Compounds of the formula ##STR1## wherein R, X1, X2, A and B are as defined herein, and their N-oxides and acid addition salts thereof, are provided which have been found to possess anti-inflammatory activity. In addition, methods for preparing such compounds, pharmaceutical compositions containing such compounds, and methods for using such compositions as anti-inflammatory agents are also provided.

Description

SUMMARY OF THE INVENTION
The present invention is directed to compounds of the formula ##STR2## and N-oxides and acid addition salts thereof, wherein X1 and X2 can be the same or different and are hydrogen, F, C1, lower alkyl, lower alkoxy, or CF3 ; R is H or lower alkyl, A is straight or branched chain alkylene of 2 to 8 carbons, and B is a 5-, 6- or 7-membered heterocyclic ring which includes a nitrogen atom, and may include the other hetero atom such as sulfur, nitrogen or oxygen. The foregoing compounds possess anti-inflammatory activity.
In addition, this invention encompasses the methods for preparing said compounds, pharmaceutical compositions containing said compounds and methods for using said compositions as anti-inflammatory agents.
The term "lower alkyl" is intended to mean a straight or branched hydrocarbon fragment of from one to six carbon atoms.
The term "lower alkoxy" is intended to mean "lower alkyl-O-".
As indicated, B is a 5-, 6- or 7-membered heterocyclic ring, which includes nitrogen and may include one other hetero atom such as nitrogen, oxygen or sulfur. Examples of such heterocyclic rings include, but are not limited to, piperidino, homopiperidino, pyrrolidino, morpholino, thiamorpholino, piperazino, N-lower alkyl substituted piperazino or N-hydroxyloweralkylpiperazino.
The "alkylene" group represented by A includes straight or branched chain radicals of 2 to 8 carbons, such as --(CH2)2 --, --(CH2)4 --, ##STR3## and the like.
Preferred are those compounds of formula I wherein X1 and X2 are the same, A contains 2 to 4 carbons, R is hydrogen, and B is a 6-membered heterocyclic ring. More preferred are those compounds wherein X1 is hydrogen, X2 is hydrogen, R is hydrogen, A contains 2 or 3 carbons, and B is piperidino, piperazinyl, N-alkylpiperazinyl or morpholinyl.
The term "acid-addition salts" is intended to mean salts which may be formed for the purpose of isolation, purification and storage, such as the oxalate salt, etc. and pharmaceutically acceptable salts meant for administration of the compound to a host, such as the hydrochloride, sulfate, acetate, citrate, etc.
The new compounds of formula I are prepared by reacting the appropriate cycloalkylone represented by formula ##STR4## with a substituted benzaldehyde of the formula ##STR5## to produce the intermediate of the formula ##STR6##
The compounds of formula IV are converted to a compound of formula I by reaction with a hydrazine of the formula ##STR7## in an organic solvent, preferably an alcohol of up to four carbon atoms at temperatures of from about 40° to about 120° C, preferably at about the reflux temperature of the solvent, for from about 1/2 hour to about 12 hours, preferably for about 4 hours.
The hydrazine of formula V is prepared by reacting a heteroalkylene halide, B-A-halo, with an excess of hydrazine H2 NNH2.
Alternatively, compounds of formula IV can be reacted with a hydroxyalkyl hydrazine of the formula ##STR8## to form the alcohol of the formula ##STR9## The alcohol of formula VII is reacted by heating with p-toluenesulfonyl chloride to form the tosylate of formula ##STR10## which in turn is treated with the heterocyclic compound of formula HB to form the compounds of formula I.
All of the starting materials in the above reactions as well as the reaction conditions and techniques are conventional in nature as will be apparent to one skilled in the art.
A compound of formula I may be converted to its N-oxide by reaction with an oxidizing agent such as hydrogen peroxide, peracetic acid and so forth.
The compounds of the present invention, their N-oxides, and their non-toxic pharmaceutically acceptable mono- or di-acid addition salts are useful as anti-inflammatory agents in mammalian species, e.g., rats and mice, as indicated by the passive cutaneous anaphylaxis test in the rat [Ref: Ovary, Z and Bier, O.G., Proc. Soc. Exp. Biol. Med. 81:584, 1952 and Goose, J. and Blair, A. M. J. N., Immunology, 16:749, 1969], when administered in amounts ranging from about 0.5 mg/kg to about 10.0 mg/kg of body weight per day. A preferred dosage regimen for optimum results is from about 1 mg to about 5 mg per kg of body weight per day, and such dosage units are employed that a total of about 35 mg to about 7 g of active ingredient are administered in a 24-hour period for a subject of about 70 kg body weight.
The compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.
The active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard of soft gelatin, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
The following examples illustrate the present invention, without, however, limiting the same thereto. All temperatures are expressed in degrees Centigrade.
EXAMPLE 1 3,3a, 4,5,6,7-Hexahydro-3-Phenyl-7-(Phenylmethylene)-2-[3-(1-piperidinyl)propyl]-2H-indazole, maleate salt (1:1)
A. 2,6-bis(phenylmethylene)cyclohexanone
A solution of 32.0 g (0.33 mole) of cyclohexanone, 70.0 g (0.66 mole) of benzaldehyde, 200 ml of ethanol and 20 ml of concentrated HCl is heated and then refluxed for one hour. Crystallization from the deep red solution occurs and after cooling the crystallized 2,6-bis(phenylmethylene)cyclohexanone is filtered and washed with cold ethanol and dried yielding 72.0 g; m.p. 114°-116° . This material is recrystallized from 120 ml of DMF (dimethylformamide) yielding 56.0 g (63%) of yellow 2,6-bis(phenylmethylene)cyclohexanone; m.p. 114°-116° .
B. n-(3-hydrazinopropyl)piperidine
Forty grams (0.20 mole) of N-(3-chloropropyl)-piperidine .sup.. HCl and 30 ml of anhydrous N2 H4 are reacted in 160 ml of ethanol by the method of Nagrody and Morris, Can. J. Chem., 47, 2001 (1969). The halide in ethanol is added as a warm solution because of its limited solubility in cold ethanol. The yield of the desired hydrazine is 13.6 g (43%); b.p. 135°-138° /18 mm. Lit. b.p. 133°-135° /20 mm.
C. 3,3a, 4,5,6,7-Hexahydro-3-phenyl-7-(phenylmethylene)-2-[3-(1-piperidinyl)propyl]-2H-indazole, maleate salt
A stirred mixture of 2,6-bis(phenylmethylene)cyclohexanone (8.8 g; 0.032 mole), 5.1 g (0.032 mole) of the above hydrazine and 80 ml of methanol is heated and the resulting solution refluxed for 4 hours. The bulk of the solvent is removed on a rotary evaporator and the viscous residue (14.1 g) is dissolved in 250 ml of ether and then extracted with 50 ml portions of water (six times). The ether phase is dried over MgSO4, filtered and the solvent evaporated to give 13.0 g of viscous base. A warm solution of the latter in 50 ml of MeCN is treated with a warm solution of 2.8 g of oxalic acid in 30 ml of MeCN. On rubbing, the crystalline oxalate salt separates; wt., after cooling overnight, 13.0 g; m.p. 178°-180° (foaming); s. 170° . Following crystallization from 25 ml of hot DMF - 80 ml MeCN, the cream-colored solid weighs 11.6 g; m.p. 172°-174° (foaming).
The oxalate salt is converted to the base (K2 CO3 ; ether extractions) and the latter (9.3 g) and 2.6 g of maleic acid are dissolved in 60 ml of warm MeCN and diluted to 600 ml with ether. After prolonged rubbing and subsequent cooling, the crystalline maleate salt slowly separates; crude yield, 8.5 g (50%); m.p. 121°-122° (s. 117° ). Crystallization from 60 ml methanol - 700 ml ether gives 7.7 g (45%) of nearly colorless product; m.p. 146°-148° .
EXAMPLE 2 3,3a, 4,5,6,7-Hexahydro-2-[3-(4-methyl-1-piperazinyl)-propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole, maleate salt (1:2)
A. 1-(3-hydrazinopropy)-4-methylpiperazine
Nineteen grams (0.05 mole) of 1-(3-bromopropyl)-4-methylpiperazine. 2HBr [prepared as described in Krapcho and Turk, J. Med. Chem., 9, 191, (1966)] is pulverized and added to a stirred solution of 16 ml (0.5 mole) of anhydrous N2 H4 in 50 ml of ethanol. The temperature rises gradually to 48° before subsiding. The mixture is then refluxed for 4 hours and kept overnight at room temperature.
The heavy lower layer is separated, extracted with ethanol, and the combined ethanol layers are concentrated in a rotary evaporator. The oily residue (11.0 g) is distilled to give 5.8 g (68%) of a colorless oil; b.p. 100°-103° /1 mm. The material is hygroscopic and picks up CO2 readily.
B. 3,3a, 4,5,6,7-Hexahydro-2-[3-(4-methyl-1-piperazinyl)-propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole maleate salt (1:2)
2,6-Bis(phenylmethylene)cyclohexanone (8.8 g; 0.032 mole) is reacted with the above hydrazine as prepared in part A (5.5 g; 0.032 mole) in 80 ml of methanol as described under Part C of Example 1 to give 16 g of crude oily base. The crude dioxalate salt weighs 16.1 g; m.p. 200°-202° (dec.). Following crystallization from 50 ml hot DMF - 100 ml MeCN, the cream colored solid weighs 13.9 g; m.p. 204°-206° (dec.).
The dioxalate salt is converted to the base (K2 CO3 ; ether extractions) and the latter (8.3 g) and 4.5 g of maleic acid are dissolved in 140 ml of warm MeCN; the solid dimaleate salt separates. After crystallizing at room temperature the mixture is cooled overnight; wt. 12.1 g (65%); m.p. 179°-181° . Crystallization from 30 ml hot DMF - 80 ml MeCN gives 10.7 g (57%) of cream colored material; m.p. 179°-181° .
EXAMPLE 3 3,3a, 4,5,6,7-Hexahydro-2-[3-(4-morpholinyl)-propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole, hydrochloride (1:1)
A. n-(3-chloropropyl)morpholine, hydrochloride
Trimethylene chlorobromide (180 g; 1.15 moles) and 150 g (1.72 moles) of morpholine are reacted in 450 ml of benzene by the method of Adams and Whitmore, JACS, 67, 736 (1945). However, instead of extracting with HCl as in the reference, the solvents are evaporated and the residue distilled to give 76.8 g of colorless oil; b.p. 112°-117° /25 mm. Lit. b.p., 113°-115° /25 mm. The product is dissolved in 1.2 1. of ether, cooled, stirred, and treated with 58 ml. of 8.2 N alcoholic HCl to precipitate the solid HCl salt; yield, 81.6 g (36%); m.p. 164°-166° .
B. n-(3-hydrazinopropyl)morpholine
The above material as prepared in part A (40 g; 0.20 mole) and 30 ml of anhydrous N2 H4 are reacted in 160 ml of ethanol by the method of Nagrody and Morris, Can. J. Chem., 47, 2001 (1969). The halide in ethanol is added as a warm solution because of its limited solubility in cold ethanol. A colorless oil is obtained; 17.7 g (56%); b.p. 115°-119° /1 mm.
C. 3,3a, 4,5,6,7-Hexahydro-2-[3-(4-morpholinyl)propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole, hydrochloride 2,6-Bis(phenylmethylene)cyclohexanone (8.8 g; 0.032 mole) and 5.2 g (0.033 mole) of the above hydrazine as prepared in part A are reacted in 80 ml of methanol as described under part C, Example 1, to give 12.8 g of a semi-solid crude base which is crystallized from 60 ml of MeCN to yield 8.2 g of pale yellow solid; m.p. 98°-100° .
A stirred suspension of the base (7.9 g) in 40 ml of MeCN is treated with 2.4 ml of 8.2 N alcoholic HCl and the resulting solution diluted to 300 ml with ether. On rubbing, the crystalline HCl salt gradually separates; crude yield, after cooling overnight, 8.0 g (55%); m.p. 134°-136° (s. 125°). Following crystallization from 40 ml warm methanol-400 ml ether, the nearly colorless product weighs 7.0 g (49%); m.p. 137°-139° .
EXAMPLES 4 to 14
Following the procedure of Example 1 but substituting for benzaldehyde in part A, the compound indicated in column I, there is obtained the corresponding compound of formula I (corresponding to Example 1) wherein each X (that is X1 and X2), and its position, is as indicated in column II:
______________________________________                                    
Example      I                II                                          
______________________________________                                    
4      o-chlorobenzaldehyde                                               
                           2-chloro                                       
5      p-chlorobenzaldehyde                                               
                           4-chloro                                       
6      p-fluorobenzaldehyde                                               
                           4-fluoro                                       
7      2-methylbenzaldehyde                                               
                           2-methyl                                       
8      3-methylbenzaldehyde                                               
                           3-methyl                                       
9      4-methylbenzaldehyde                                               
                           4-methyl                                       
10     2-methoxybenzaldehyde                                              
                           2-methoxy                                      
11     3-methoxybenzaldehyde                                              
                           3-methoxy                                      
12     4-methoxybenzaldehyde                                              
                           4-methoxy                                      
13     4-butoxybenzaldehyde                                               
                           4-butoxy                                       
14     3-trifluoromethylbenzaldehyde                                      
                           3-trifluoromethyl                              
______________________________________
EXAMPLES 15 to 25
Following the procedure of Example 1 and Example 2 but substituting for benzaldehyde in Example 1 part A, the compound indicated in column I, there is obtained the corresponding compound of formula I (corresponding to the compound formed in Example 2) wherein each X (that is X1 and X2), and its position, is as indicated in column II:
______________________________________                                    
Example                                                                   
        I                   II                                            
______________________________________                                    
15     o-chlorobenzaldehyde                                               
                           2-chloro                                       
16     p-chlorobenzaldehyde                                               
                           4-chloro                                       
17     p-fluorobenzaldehyde                                               
                           4-fluoro                                       
18     2-ethylbenzaldehyde 2-ethyl                                        
19     3-methylbenzaldehyde                                               
                           3-methyl                                       
20     4-propylbenzaldehyde                                               
                           4-propyl                                       
21     2-methoxybenzaldehyde                                              
                           2-methoxy                                      
22     3-ethoxybenzaldehyde                                               
                           3-ethoxy                                       
23     4-propoxybenzaldehyde                                              
                           4-propoxy                                      
24     3-butoxybenzaldehyde                                               
                           3-butoxy                                       
25     4-trifluoromethylbenzaldehyde                                      
                           4-trifluoromethyl                              
______________________________________
EXAMPLES 26 to 36
Following the procedure of Example 1 and Example 3 but substituting for benzaldehyde in Example 1 part A, the compound indicated in column I, there is obtained the corresponding compound of formula I (corresponding to the compounds formed in Example 3) wherein each X (that is X1 and X2), and its position, is as indicated in column II:
______________________________________                                    
Example      I                II                                          
______________________________________                                    
26     o-chlorobenzaldehyde                                               
                           2-chloro                                       
27     p-chlorobenzaldehyde                                               
                           4-chloro                                       
28     p-fluorobenzaldehyde                                               
                           4-fluoro                                       
29     2-methylbenzaldehyde                                               
                           2-methyl                                       
30     3-methylbenzaldehyde                                               
                           3-methyl                                       
31     4-methylbenzaldehyde                                               
                           4-methyl                                       
32     2-methoxybenzaldehyde                                              
                           2-methoxy                                      
33     3-methoxybenzaldehyde                                              
                           3-methoxy                                      
34     4-methoxybenzaldehyde                                              
                           4-methoxy                                      
35     4-butoxybenzaldehyde                                               
                           4-butoxy                                       
36     3-trifluoromethylbenzaldehyde                                      
                           3-trifluoromethyl                              
______________________________________
EXAMPLES 37 - 57
Following the procedure of Example 1 but substituting for N-(3-chloropropyl)piperidine in part B, the compound indicated in column I, there is obtained the corresponding compound of formula I (corresponding to Example 1) wherein -A-B is the group indicated in column II:
__________________________________________________________________________
Ex. No.                                                                   
        I                   II                                            
__________________________________________________________________________
37                                                                        
       ##STR11##                                                          
                           ##STR12##                                      
38                                                                        
       ##STR13##                                                          
                           ##STR14##                                      
39                                                                        
       ##STR15##                                                          
                           ##STR16##                                      
40                                                                        
       ##STR17##                                                          
                           ##STR18##                                      
41                                                                        
       ##STR19##                                                          
                           ##STR20##                                      
42                                                                        
       ##STR21##                                                          
                           ##STR22##                                      
43                                                                        
       ##STR23##                                                          
                           ##STR24##                                      
44                                                                        
       ##STR25##                                                          
                           ##STR26##                                      
45                                                                        
       ##STR27##                                                          
                           ##STR28##                                      
46                                                                        
       ##STR29##                                                          
                           ##STR30##                                      
47                                                                        
       ##STR31##                                                          
                           ##STR32##                                      
48                                                                        
       ##STR33##                                                          
                           ##STR34##                                      
49                                                                        
       ##STR35##                                                          
                           ##STR36##                                      
50                                                                        
       ##STR37##                                                          
                           ##STR38##                                      
51                                                                        
       ##STR39##                                                          
                           ##STR40##                                      
52                                                                        
       ##STR41##                                                          
                           ##STR42##                                      
53                                                                        
       ##STR43##                                                          
                           ##STR44##                                      
54                                                                        
       ##STR45##                                                          
                           ##STR46##                                      
55                                                                        
       ##STR47##                                                          
                           ##STR48##                                      
56                                                                        
       ##STR49##                                                          
                           ##STR50##                                      
57                                                                        
       ##STR51##                                                          
                           ##STR52##                                      
__________________________________________________________________________
EXAMPLES 58 to 63
Following the procedure of Example 1A, upon substituting in place of the cyclohexanone, one of the following:
4-methylcyclohexanone
4-ethylcyclohexanone
4-n-propylcyclohexanone
4-t-butylcyclohexanone
3-methylcyclohexanone
3-ethylcyclohexanone
one obtains the following:
2,6-bis(phenylmethylene)(4-methylcyclohexanone)
2,6-bis(phenylmethylene)(4-ethylcyclohexanone)
2,6-bis(phenylmethylene)(4-n-propylcyclohexanone)
2,6-bis(phenylmethylene)(4-t-butylcyclohexanone)
2,6-bis(phenylmethylene)(3-methylcyclohexanone)
2,6-bis(phenylmethylene)(3-ethylcyclohexanone)
Upon substituting the above compound in Example 1 in place of the 2,6-bis(phenylmethylene)cyclohexanone, one obtains the following:
______________________________________                                    
 ##STR53##                                                                
            R                                                             
______________________________________                                    
58.       5-methyl                                                        
59.       5-ethyl                                                         
60.       5-n-propyl                                                      
61.       5-t-butyl                                                       
62.       4 and/or 6-methyl                                               
63.       4 and/or 6-ethyl                                                
______________________________________
EXAMPLES 64 to 69
Following the procedure of Example 1A, upon substituting in place of the cyclohexanone, one of the following:
4-methylcyclohexanone
4-ethylcyclohexanone
4-n-propylcyclohexanone
4-t-butylcyclohexanone
3-methylcyclohexanone
3-ethylcyclohexanone
one obtains the following:
2,6-bis(phenylmethylene)(4-methylcyclohexanone)
2,6-bis(phenylmethylene)(4-ethylcyclohexanone
2,6-bis(phenylmethylene)(4-n-propylcyclohexanone)
2,6-bis(phenylmethylene)(4-t-butylcyclohexanone)
2,6-bis(phenylmethylene)(3-methylcyclohexanone)
2,6-bis(phenylmethylene)(3-ethylcyclohexanone)
Upon substituting the above compounds in Example 2C in place of the 2,6-bis(phenylmethylene)cyclohexanone, one obtains the following:
______________________________________                                    
 ##STR54##                                                                
            R                                                             
______________________________________                                    
64.       5-methyl                                                        
65.       5-ethyl                                                         
66.       5-n-propyl                                                      
67.       5-t-butyl                                                       
68.       4 and/or 6-methyl                                               
69.       4 and/or 6-ethyl                                                
______________________________________
EXAMPLES 70 to 75
Following the procedure of Example 1A, upon substituting in place of the cyclohexanone, one of the following:
4-methylcyclohexanone
4-ethylcyclohexanone
4-n-propylcyclohexanone
4-n-butylcyclohexanone
3-methylcyclohexanone
3-ethylcyclohexanone
one obtains the following:
2,6-bis(phenylmethylene)(4-methylcyclohexanone)
2,6-bis(phenylmethylene)(4-ethylcyclohexanone)
2,6-bis(phenylmethylene)(4-n-propylcyclohexanone)
2,6-bis(phenylmethylene)(4-n-butylcyclohexanone)
2,6-bis(phenylmethylene)(3-methylcyclohexanone)
2,6-bis(phenylmethylene)(3-ethylcyclohexanone)
Upon substituting the above compounds in Example 3C in place of the 2,6-bis(phenylmethylene)cyclohexanone, one obtains the following:
______________________________________                                    
 ##STR55##                                                                
            R                                                             
______________________________________                                    
70.       5-methyl                                                        
71.       5-ethyl                                                         
72.       5-n-propyl                                                      
73.       5-n-butyl                                                       
74.       4 and/or 6-methyl                                               
75.       4 and/or 6-ethyl                                                
______________________________________
EXAMPLES 76-88
Following the procedure of Example 1, but substituting for the benzaldehyde (in part A of Example 1), the compound indicated in column I, substituting for the cyclohexanone, the compound indicated in column II, substituting for the N-(3-chloropropylpiperidine.sup.. HCl, the compound listed in column III, there is obtained the corresponding compound of formula I wherein X1, X2, R, A and B are as indicated in column IV:
__________________________________________________________________________
I       II   III              IV                                          
 ##STR56##                                                                
         ##STR57##                                                        
                               ##STR58##                                  
__________________________________________________________________________
Ex.                                                                       
    X.sub.1                                                               
         R    XAB              X.sub.1                                    
                                    X.sub.2                               
                                          R     A    B                    
__________________________________________________________________________
76 o-F  H                                                                 
              ##STR59##       o-F  same as X.sub.1                        
                                         H     (CH.sub.2).sub.3           
                                                     ##STR60##            
77 p-Cl 4-C.sub.2 H.sub.5                                                 
              ##STR61##       p-Cl "     5-C.sub.2 H.sub.5                
                                               (CH.sub.2).sub.4           
                                                     ##STR62##            
78 3-C.sub.2 H.sub.5                                                      
        4-C.sub.3 H.sub.7                                                 
              ##STR63##       3-C.sub.2 H.sub.5                           
                                   "     5-C.sub.3 H.sub.7                
                                               (CH.sub.2).sub.2           
                                                     ##STR64##            
79 4-CH.sub.3 O                                                           
        4-C.sub.4 H.sub.9                                                 
              ##STR65##       4-CH.sub.3 O                                
                                   "     5-C.sub.4 H.sub.9                
                                               CH.sub.2                   
                                                     ##STR66##            
80 4-CF.sub.3                                                             
        3-CH.sub.3                                                        
              ##STR67##       4-CF.sub.3                                  
                                   "     4- and/or  6-CH.sub.3            
                                               (CH.sub.2).sub.3           
                                                     ##STR68##            
81 3-C.sub.4 H.sub.9 O                                                    
        3-CH.sub.3                                                        
              ##STR69##       3-C.sub.4 H.sub.9 0                         
                                   "     4- and/or  6-CH.sub.3            
                                               (CH.sub.2).sub.2           
                                                     ##STR70##            
82 H    3-C.sub.2 H.sub.5                                                 
              ##STR71##       H    "     4- and/or  6-C.sub.2 H.sub.5     
                                               (CH.sub.2).sub.4           
                                                     ##STR72##            
83 3-C.sub.3 H.sub.7 O                                                    
        4-C.sub.3 H.sub.7                                                 
              ##STR73##       3-C.sub.3 H.sub.7 O                         
                                   "     5-C.sub.3 H.sub.7                
                                               (CH.sub.2).sub.3           
                                                     ##STR74##            
84 2-C.sub.2 H.sub.5                                                      
        H                                                                 
              ##STR75##       2-C.sub.2 H.sub.5                           
                                   "     H     (CH.sub.2).sub.3           
                                                     ##STR76##            
85 3-C.sub.2 H.sub.5 O                                                    
        4-C.sub. 4 H.sub.9                                                
              ##STR77##       3-C.sub.2 H.sub.5 O                         
                                   "     5-C.sub.4 H.sub.9                
                                               (CH.sub.2).sub.2           
                                                     ##STR78##            
86 4-C.sub.5 H.sub.11                                                     
        H                                                                 
              ##STR79##       4-C.sub.5 H.sub.11                          
                                   "     H     (CH.sub.2).sub.3           
                                                     ##STR80##            
87 4-C.sub.6 H.sub.13 O                                                   
        3-C.sub.5 H.sub.11                                                
              ##STR81##       4-C.sub.6 H.sub.13 O                        
                                   "     4- and/or 6-C.sub.5 H.sub.11     
                                               (CH.sub.2).sub.4           
                                                    N                     
88 o-Cl 4-C.sub.6 H.sub.13                                                
              ##STR82##       o-Cl "     5-C.sub.6 H.sub.13               
                                               (CH.sub.2).sub.2           
                                                     ##STR83##            
__________________________________________________________________________
EXAMPLE 89 Preparation of capsule formulation 
______________________________________                                    
                         Milligrams                                       
Ingredient               per Capsule                                      
______________________________________                                    
3,3a,4,6,7-hexahydro-3-phenyl-7-                                          
(phenylmethylene)-2-[3-(1-piperidinyl)-                                   
propyl]-2H-indazole, maleate salt (1:1)                                   
                         400                                              
Starch                   80                                               
Magnesium stearate       5                                                
______________________________________
The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of 485 milligrams per capsule.
EXAMPLE 90 Preparation of tablet formation 
______________________________________                                    
                         Milligrams                                       
Ingredient               per Tablet                                       
______________________________________                                    
3,3a,4,6,7-hexahydro-2-[3-(4-methyl-                                      
1-piperazinyl)propyl]-3-phenyl-7-                                         
(phenylmethylene)-2H-indazole,                                            
maleate salt (1:2)       300                                              
Lactose                  200                                              
Corn starch (for mix)    50                                               
Corn starch (for paste)  50                                               
Magnesium stearate       6                                                
______________________________________
The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120° F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.
EXAMPLE 91 Preparation of oral syrup formulation 
______________________________________                                    
Ingredient               Amount                                           
______________________________________                                    
3,3a,4,5,6,7-hexahydro-2-[3-(4-morpho-                                    
linyl)-propyl]-3-phenyl-7-(phenyl-                                        
methylene)-2H-indazole, hydrochloride                                     
(1:1)                    500     mg.                                      
Sorbitol solution (70% N.F.)                                              
                         40      ml.                                      
Sodium benzoate          150     mg.                                      
Sucaryl                  90      mg.                                      
Saccharin                10      mg.                                      
Red Dye (F.C. & C. No. 2)                                                 
                         10      mg.                                      
Cherry flavor            50      mg.                                      
Distilled water qs to    100     ml.                                      
______________________________________
The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.
Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.

Claims (15)

What is claimed is:
1. A compound of the formula ##STR84##wherein X1 and X2 are the same or different and are selected from the group consisting of hydrogen, F, Cl, lower alkyl, lower alkoxy, or CF3 ; R is selected from the group consisting of hydrogen or lower alkyl, A is a straight or branched chain alkylene group of from 2 to about 8 carbons, and B is a 5-, 6-, or 7-membered heterocyclic ring selected from the group consisting of piperidinyl, homopiperidinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl, piperazinyl, N-lower alkylpiperazinyl and N-hydroxy-lower alkylpiperazinyl; and N-oxides and pharmaceutically acceptable acid addition salts thereof.
2. A compound as defined in claim 1 wherein X1 and X2 are the same.
3. A compound as defined in claim 1 wherein X1 and X2 are hydrogen.
4. A compound as defined in claim 1 wherein one of X1 and X2 is hydrogen.
5. A compound as defined in claim 1 wherein X1 and X2 are the same or different and are selected from the group consisting of hydrogen, lower alkyl, F or Cl.
6. A compound as defined in claim 1 wherein X1 and X2 are the same or different and are selected from the group consisting of hydrogen, lower alkoxy or CF3.
7. A compound as defined in claim 1 wherein R is hydrogen.
8. A compound as defined in claim 1 wherein R is lower alkyl.
9. A compound as defined in claim 1 wherein A contains 2 to 4 carbons.
10. A compound as defined in claim 1 wherein B is morpholinyl, piperazinyl or piperidinyl.
11. A compound of claim 1 having the name 3,3a,4,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2-[3-(1-piperidinyl)propyl]-2H-indazole or its maleate salt.
12. A compound as defined in claim 1 having the name 3,3a,4,6,7-hexahydro-2-[3-(4-methylpiperazinyl)-propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole or its maleate salt.
13. A compound as defined in claim 1 having the name 3,3a,4,5,6,7-hexahydro-2-[3-(4-morpholinyl)propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole or its hydrochloride salt.
14. An anti-inflamatory composition comprising an effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier.
15. A method of treating inflammation in mammalian species, which comprises administering to a mammalian host a therapeutic amount of a compound as defined in claim 1.
US05/603,222 1975-08-08 1975-08-08 2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles Expired - Lifetime US4004007A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US05/603,222 US4004007A (en) 1975-08-08 1975-08-08 2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles
GB31485/76A GB1541079A (en) 1975-08-08 1976-07-28 2-heterocyclylalkyl-3,3a,4,5,6,7-hexa hydro-3-phenyl-7-benzylidene-2h-indazoles
CA258,397A CA1076575A (en) 1975-08-08 1976-08-04 2-heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2h-indazoles
FR7623991A FR2320094A1 (en) 1975-08-08 1976-08-05 INDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USES
DE19762635278 DE2635278A1 (en) 1975-08-08 1976-08-05 3,3A, 4,5,6,7-HEXAHYDRO-3-PHENYL-7-PHENYLMETHYLEN-2H-INDAZOLE, METHOD FOR THEIR MANUFACTURING AND DRUGS CONTAINING THESE COMPOUNDS
JP51094414A JPS5914025B2 (en) 1975-08-08 1976-08-07 Hexahydro-2H-indazole derivative and its production method
BE0/196446A BE877886Q (en) 1975-08-08 1979-07-25 2-HETEROCYCLICALKYL-3-3A, 4, 5, 6, 7-HEXAHYDRO-3-PHENYL-7- (PHENYLMETHYLENE) -2H-INDAZOLES
HK746/79A HK74679A (en) 1975-08-08 1979-10-25 2-heterocyclylalkyl-3,3a-4-5-6-7-hexahydro-3-phenyl-7-benzylidene-2h-indazoles

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US05/603,222 US4004007A (en) 1975-08-08 1975-08-08 2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles

Publications (1)

Publication Number Publication Date
US4004007A true US4004007A (en) 1977-01-18

Family

ID=24414537

Family Applications (1)

Application Number Title Priority Date Filing Date
US05/603,222 Expired - Lifetime US4004007A (en) 1975-08-08 1975-08-08 2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles

Country Status (8)

Country Link
US (1) US4004007A (en)
JP (1) JPS5914025B2 (en)
BE (1) BE877886Q (en)
CA (1) CA1076575A (en)
DE (1) DE2635278A1 (en)
FR (1) FR2320094A1 (en)
GB (1) GB1541079A (en)
HK (1) HK74679A (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3808272A1 (en) * 1988-03-12 1989-09-28 Lemfoerder Metallwaren Ag BEARING FOR THE GEAR SHIFT LEVER IN MOTOR VEHICLES
EP2365973A1 (en) * 2008-11-13 2011-09-21 Schering Corporation Gamma secretase modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3852279A (en) * 1973-03-12 1974-12-03 Squibb & Sons Inc 7-substituted -3,3a,4,5,6,7-hexahydro-3-substituted-2h- pyrazolo (4,3-c)pyridines
US3897420A (en) * 1973-06-28 1975-07-29 Squibb & Sons Inc 2-Aminoalkyl-7-substituted-3,3a,4,5,6,7-hexahydro-3-substituted-2H-pyrazolo(4,3-c)pyridines

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1065324A (en) * 1974-05-13 1979-10-30 E.R. Squibb And Sons 2-aminoalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2h-indazoles and related cyclohepta (c) pyrazoles and cyclopentapyrazoles

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3852279A (en) * 1973-03-12 1974-12-03 Squibb & Sons Inc 7-substituted -3,3a,4,5,6,7-hexahydro-3-substituted-2h- pyrazolo (4,3-c)pyridines
US3897420A (en) * 1973-06-28 1975-07-29 Squibb & Sons Inc 2-Aminoalkyl-7-substituted-3,3a,4,5,6,7-hexahydro-3-substituted-2H-pyrazolo(4,3-c)pyridines

Also Published As

Publication number Publication date
FR2320094B1 (en) 1978-11-17
DE2635278A1 (en) 1977-02-17
JPS5914025B2 (en) 1984-04-02
JPS5223074A (en) 1977-02-21
BE877886Q (en) 1979-11-16
HK74679A (en) 1979-11-02
GB1541079A (en) 1979-02-21
FR2320094A1 (en) 1977-03-04
CA1076575A (en) 1980-04-29

Similar Documents

Publication Publication Date Title
US4001263A (en) 5-Aryl-1,2,3,4-tetrahydro-γ-carbolines
US3852279A (en) 7-substituted -3,3a,4,5,6,7-hexahydro-3-substituted-2h- pyrazolo (4,3-c)pyridines
HU211144A9 (en) Cyclic amine derivatives and their pharmaceutical use
JP2001512118A (en) Pyridyl- and pyrimidyl heterocyclic compounds that inhibit oxidosqualene-cyclase
US4066648A (en) Isochroman derivatives
US3931197A (en) Substituted piperidine derivatives
US4539322A (en) Dihydropyridine derivatives and their use in treating heart conditions and hypertension
JPH05502682A (en) piperazine derivatives
US4048182A (en) Derivatives of imidazo [4,5-b]pyridines
US4853391A (en) Pyrido[1,2-a]indoles and their use as cardiovascular
US4146629A (en) 4-arylpiperidine derivatives
US4007191A (en) 2-(Piperidinyl or tetrahydropyridinyl)-alkyl)-2,3-dihydro-3-hydroxy-1H-benz(DE)isoquinolin-1-ones
US3459767A (en) Aminomethylindoles
US4004007A (en) 2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles
US4446141A (en) Hypotensive piperidine derivatives
US3931222A (en) Tetrahydro-carbazole derivates
US4616017A (en) Aminohydroxypropoxy substituted aryl compounds
US3897420A (en) 2-Aminoalkyl-7-substituted-3,3a,4,5,6,7-hexahydro-3-substituted-2H-pyrazolo(4,3-c)pyridines
US4247549A (en) Piperazine-1-carboxylic acid esters possessing antidepressant or analgesic activity
US4521537A (en) Spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine and -3'-pyrrolidine] compounds and their use as antihypertensive agents
US4447439A (en) 2-Cyclic amino-2-(1,2-benzisoxazol-3-yl)acetic acid ester derivatives, process for the preparation thereof and composition containing the same
US4012373A (en) Pyrazolo[3',4'-2,3]pyrido[4,5-e]b-benzo-1,5-diazepinones
US3810905A (en) Pyrazolo(3,4-b)pyridine-5-carboxamides
US4022779A (en) Amino derivatives of pyrido(3,4-b)pyrazine carboxylic acids and esters
US3931169A (en) 5-Substituted-pyrazolo(4,3-c)pyridines